Neuroprotective Effects of Alpha-Lipoic Acid and Ferulic Acid on Peripheral Neuropathic Pain in Rats
DOI:
https://doi.org/10.63682/jns.v14i32S.7925Keywords:
Peripheral Neuropathic Pain, Chronic Constriction Injury, Alpha-Lipoic Acid, Ferulic Acid, Antioxidant Therapy, TNF-αAbstract
Background: Increased nociceptive sensitivity and neuroinflammation are hallmarks of peripheral neuropathic pain (PNP), a chronic and incapacitating condition brought on by nerve damage or metabolic abnormalities. Rats' chronic constriction injury (CCI) model accurately mimics human PNP. Natural antioxidants ferulic acid (FA) and alpha-lipoic acid (ALA) have strong anti-inflammatory and neuroprotective effects. In a CCI-induced PNP model in rats, this study examined and contrasted the therapeutic potential of ALA, FA, and their combination with the common medication gabapentin.
Methods: Five groups (n=6) of adult Wistar rats were created: Disease Control, Gabapentin (30 mg/kg, i.p.), alpha-lipoic acid (25 mg/kg, p.o.), ferulic acid (10 mg/kg, p.o.), and a combination of alpha-lipoic acid + ferulic acid (12 mg/kg + 5 mg/kg, p.o.). Mechanical allodynia (von Frey), cold allodynia (acetone), thermal hyperalgesia (hot plate), and mechanical hyperalgesia (pinprick) tests were among the behavioural evaluations. In sciatic nerve homogenates, biochemical analyses determined the levels of SOD, CAT, GSH, MDA, and TNF-α. Axonal integrity and inflammation were evaluated by histopathological analysis.
Results: Pro-inflammatory markers, oxidative stress, and nociceptive behaviour were all markedly elevated by CCI. ALA or FA monotherapy produced modest gains. However, their combined effects closely mirrored those of gabapentin, significantly reducing pain behaviour and normalising oxidative and inflammatory parameters. Better axonal preservation in combination-treated rats was confirmed by histology.
Conclusion: The synergistic neuroprotective and antioxidant effects of ALA and FA, particularly when combined, point to their potential as an adjuvant or alternative therapy for management of PNP.
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Jensen TS, Baron R, Haanpää M, Kalso E, Loeser JD, Rice AS, Treede RD. A new definition of neuropathic pain. Pain. 2011;152(10):2204–2205. https://doi.org/10.1016/j.pain.2011.10.026.
Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, Freeman R, Truini A, Attal N, Finnerup NB, Eccleston C, Kalso E, Bennett DL, Dworkin RH, Raja SN. Neuropathic pain. Lancet Neurol. 2017;16(9):807–821. https://doi.org/10.1016/S1474-4422(17)30102-5.
Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, Hansson P, Hughes R, Nurmikko T, Serra J. Neuropathic pain: Redefinition and a grading system for clinical and research purposes. Neurology. 2008;70(18):1630–1635. https://doi.org/10.1212/01.wnl.0000281689.29778.59.
Baron R, Binder A, Wasner G. Neuropathic pain: Diagnosis, pathophysiological mechanisms, and treatment. Nat Rev Neurol. 2010;6(10):507–517. https://doi.org/10.1038/nrneurol.2010.24.
Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, Bushnell MC, Farrar JT, Galer BS, Haythornthwaite JA, Hewitt DJ, Loeser JD, Max MB, Saltarelli M, Schmader KE, Stein C, Thompson D, Turk DC, Wallace MS, Watkins LR, Weinstein SM. Advances in neuropathic pain: Diagnosis, mechanisms, and treatment recommendations. Neurology. 2003;60(1):17–24. https://doi.org/10.1212/01.WNL.0000091115.08711.E4.
van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: A systematic review of epidemiological studies. Pain. 2014;155(4):654–662. https://doi.org/10.1016/j.pain.2014.04.003.
Ziegler D, Tesfaye S, Spallone V, Gurieva I, Al Kaabi J, Pfeiffer AFH. Screening, diagnosis and management of diabetic sensory polyneuropathy in clinical practice: International expert consensus recommendations. Diabetes Metab Res Rev. 2014;30(8):737–745. https://doi.org/10.1002/dmrr.2512.
Finnerup NB, Norrbrink C, Trok K, Piehl F, Johannesen IL, Sorensen JC, Werhagen L, Jensen TS. Phenotypes and predictors of pain following traumatic spinal cord injury: A prospective study. Lancet Neurol. 2021;20(6):493–504. https://doi.org/10.1016/S1474-4422(21)00093-5.
Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1988;33(1):87–107. doi:10.1016/0304-3959(88)90209-6.
Salvemini D, Little JW, Doyle T, Neumann WL. Roles of reactive oxygen and nitrogen species in pain. Free Radic Biol Med. 2011;51(5):951–966. doi:10.1016/j.freeradbiomed.2011.01.026.
Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain. 2000;87(2):149–158. doi:10.1016/S0304-3959(00)00276-1.
Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta. 2009;1790(10):1149–1160. https://doi.org/10.1016/j.bbagen.2009.07.026
Mishra V, Palanivel R, Mourya D, Pattnaik BR, Kumar P, Kar A. Ferulic acid alleviates neuropathic pain in rats by reducing oxidative stress and neuroinflammation. Neurochem Res. 2022;47(3):612–625. https://doi.org/10.1007/s11064-021-03485-2
Obrosova IG. Increased sorbitol pathway activity generates oxidative stress in tissue sites for diabetic complications. Antioxid Redox Signal. 2005;7(11-12):1543–1552. https://doi.org/10.1089/ars.2005.7.1543
Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004;21(2):114–121. https://doi.org/10.1111/j.1464-5491.2004.01109.
Zhang WJ, Wei H, Frei B. Alpha-lipoic acid attenuates LPS-induced inflammatory responses by activating the PI3K/Akt signaling pathway. Proc Natl Acad Sci USA. 2007;104(10):4077–4082. https://doi.org/10.1073/pnas.0611335104
Moura FA, de Andrade KQ, dos Santos JC, Araújo OR, Goulart MO. Antioxidant therapy for the treatment of inflammatory bowel disease: does it work? Redox Biol. 2014;6:617–639. https://doi.org/10.1016/j.redox.2014.10.006
Srinivasan M, Sudheer AR, Menon VP. Ferulic Acid: Therapeutic potential through its antioxidant property. J Clin Biochem Nutr. 2007;40(2):92–100. https://doi.org/10.3164/jcbn.40.92
Kanski J, Aksenova M, Stoyanova A, Butterfield DA. Ferulic acid antioxidant protection against hydroxyl and peroxyl radical oxidation in synaptosomal and neuronal cell culture systems. J Nutr Biochem. 2002;13(5):273–281. https://doi.org/10.1016/S0955-2863(02)00173-6
Li J, Chen X, Lu X, Zhang C, Shi Q, Feng L. Pregabalin treatment of peripheral nerve damage in a murine diabetic peripheral neuropathy model. Acta Endocrinol (Bucharest), 2018; 14(3):294.
Gupta, S., Sherikar, A., Upaganlawar, A., Upasani, C. Neuroprotective effects of α-Lipoic acid alone and in combination with ferulic acid in diabetic neuropathy induced rats. DYSONA - Life Science, 2020; 1(3): 102-112. doi: 10.30493/dls.2020.243982.
Flecknell PA. Laboratory Animal Anaesthesia. 4th ed. London: Academic Press; 2015. p. 157–180.
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53(1):55–63. doi:10.1016/0165-0270(94)90144-9.
Lee J, et al. Analgesic effects of natural compounds in neuropathic pain models. Biomed Pharmacother. 2019;112:108709.
Yoon YW, et al. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain. 1994;59(3):369–76.
Li Y, et al. Antinociceptive activity of herbal formulations in neuropathic pain. J Ethnopharmacol. 2019;237:153–62.
Bischofs IB, Kobal G, Geisslinger G, Brune K. Experimental models of hyperalgesia and allodynia. In: Brune K, Handwerker HO, editors. Pharmacology of Pain. Springer; 2004. p. 145–62.
Levy D, Zochodne DW. Increased mRNA expression of the B1 and B2 bradykinin receptors and antinociceptive effects of their antagonists in an animal model of neuropathic pain. Pain. 2000;86(3):265–71. doi:10.1016/S0304-3959(00)00252-6.
Jibira Y, Alhassan AJ, Yaqub LS, Adamu H, Leko BA. Neuroprotective effect of Moringa oleifera seed oil against sodium arsenite-induced neurotoxicity in Wistar rats. Metab Brain Dis. 2020;35(8):1305–14. doi:10.1007/s11011-020-00591-2.
Slater TF, Sawyer BC. The stimulatory effects of carbon tetrachloride and other halogenoalkanes on peroxidation in rat liver fractions in vitro. Biochem J. 1971;123(5):823–8. doi:10.1042/bj1230823.
Moron MS, Depierre JW, Mannervik B. Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta. 1979;582(1):67–78. doi:10.1016/0304-4165(79)90289-7.
Misra HP, Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972;247(10):3170–5.
Aebi H. Catalase in vitro. Methods Enzymol. 1984;105:121–6. doi:10.1016/S0076-6879(84)05016-3.
Murthy CRK, Rama Rao KV, Reddy PV. Oxidative stress and antioxidants in epilepsy. Clin Chim Acta. 2005;356(1-2):1–21. doi:10.1016/j.cccn.2004.12.009.
Muthuraman A, Rishitha N, Singla S. Reversal of paclitaxel induced neuropathic pain by piracetam and vinpocetine in rats. Indian J Pharmacol. 2011;43(5):507–512. https://doi.org/10.4103/0253-7613.84972
Singh SK, Rai R, Yadav A, Rai R. Antiallodynic and antihyperalgesic activities of thymoquinone in experimental neuropathic pain. J Ayurveda Integr Med. 2020;11(4):522–528. https://doi.org/10.1016/j.jaim.2019.08.004
Finnerup NB, Kuner R, Jensen TS. Neuropathic pain: from mechanisms to treatment. Physiol Rev. 2021;101(1):259-301.
Zhang Y, Dong H, Wang M, et al. Oxidative stress and neuropathic pain: current knowledge and the potential of antioxidants. Pharmacol Res. 2022;175:106007.
Challa SR. Surgical animal models of neuropathic pain: pros and cons. Int J Neurosci. 2015;125(3):170-174.
Kumar A, Kaundal RK, Iyer S, Sharma SS. Effects of alpha-lipoic acid on the development of neuropathy in streptozotocin-induced diabetic rats. Am J Pharmacol Toxicol. 2020;15(3):112-119.
Liu T, Gao YJ, Ji RR. Emerging roles of cytokines in chronic pain. Nat Rev Neurosci. 019;20(10):607-621.
Bhatt V, Vyas BA, Suthar MP, et al. Protective role of ferulic acid in neuropathic pain through inhibition of oxidative stress and neuroinflammation. J Ethnopharmacol. 2022;281:114509.
Singh R, Gupta R, Khatri D, Sharma SS. Neuroprotective effect of resveratrol through anti-oxidative and anti-inflammatory mechanisms in CCI-induced neuropathic pain in rats. Mol Neurobiol. 2020;57(6):2541-2555.
Ilari S, Palmieri F, Florio T, et al. Antioxidant enzymes and mitochondrial dysfunction: potential targets in neuropathic pain. Antioxidants. 2020;9(12):1223.
Chen Y, Chen J, Yang Z, et al. Role of oxidative stress and antioxidant therapy in diabetic neuropathy: a systematic review. Oxid Med Cell Longev. 2021;2021:9942567.
Patil SP, Jain PD, Pal SC. Role of natural antioxidants in neuropathic pain: insights into mechanisms. Curr Neuropharmacol. 2021;19(4):501-517.
Czeschik JC, Hagenacker T, Schafers M, Busselberg D. TNF-alpha differentially modulates ion channels of nociceptive neurons. Neurosci Lett. 2008;434(3):293-298.
Noh MC, Park J, Lee S, et al. Interleukin-1β enhances the expression of CaV2.2 channels in dorsal root ganglia neurons through MAPK pathways. Neuroscience. 2019;401:97-110.
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